Ethers containing a hydrophenanthrene nucleus

ABSTRACT

ETHERS OF TETRAHYDRO, HEXAHYDRO, AND OCTAHYDROPHENANTHRENE AND DERIVATIVES THEREOF.

United States atent 3,636,071 ETHERS CONTAINING A HYDROPHEN- ANTHRENENUCLEUS John A. Edwards, Los Altos, (Ialifi, assignor to SyntexCorporation, Panama, Panama No Drawing. Filed Oct. 26, 1966, Ser. No.589,494 Int. Cl. C07c 69/76- US. Cl. 260-4685 7 Claims ABSTRACT OF THEDISCLOSURE Ethers of tetrahydro, hexahydro, and octahydrophenanthreneand derivatives thereof.

This invention relates to novel ethers containing a hydrophenanthrenenucleus and to a method for the preparation thereof. More particularly,this invention relates to novel ethers of tetrahydro, hexahydro andoctahydrophenanthrene and derivatives thereof, as represented by thefollowing formulas:

R R I M 2 2 11 C2H5 H i H R R 0 V wherein respectively. By the termacyloxymethyl is meant the group ice wherein R is a straight or branchedchain hydrocarbon group containing from one to six carbon atoms,inclusive.

The novel compounds of Formulas A through D possess hormonal propertiescharacteristic of estrogenic agents and are useful in fertility controland the management of various menstrual conditions such as menopausesyndrome. In addition, they also possess hormonal propertiescharacteristic of anti-fertility agents and show a marked separationbetween these activities, e.g. anti-fertility activity and estrogenicactivity. The anti-fertility activity of the tetrahydropyran-2yl andtetrahydrofuran-2'-yl compounds of the above formulas is higher whiletheir estrogenic activity is lower than the parent compound. Thesecompounds mainly effect ovum development and/ or transport of zygotes inthe oviduct. In other words, they are effective anti-fertility agentswith low estrogenicity.

The compounds of the present invention are administered via usualroutes, i.e. orally or parenterally, in pharmaceautically acceptablecompositions at dosage rates of from 0.5 to 5 mg./kg./day. However,dosage rates below or above this range can also be used; the mostfavorable dosage rate and administration route being conditioned uponthe purpose for which it is administered and the response thereto.

The novel ethers of the present invention are obtained from acorresponding 7-hydroxy containing parent compound as shown in thefollowing sequence:

i W M 2 NW @2115 OgH Z E Z H HO R O Z 2 wherein R is carboalkoxy, cyano,amido, carbothioalkyl, acetyl,

formyl, acyloxymethyl or methyl;

Z is a carbon-carbon single bond or a carbon-carbon double bond;

Z is a carbon-carbon single bond or a carbon-carbon double bond, Z beinga single bond when Z is a single bond; and all other substituents are asdefined hereinabove.

The wavy line indicates both cis and trans isomers. The free 7-hydroxycontaining parent compound of Formula E is converted to the novel7-ethers by the following etherification procedures.

For the preparation of the cyclopentyl ethers of Formula F of thepresent invention, the free 7-hydroxy containing parent compound isreacted, under substantially anhydrous conditions, with an alkali metalhydride, such as sodium hydride and the like, and cyclopentyl chloride,bromide or iodide, in an inert solvent such as benzene, Xylene,tetrahydrofuran and the like, at a temperature of from 25 C. to thereflux temperature of the solvent, and preferably at the refluxtemperature, for from about 1 to about 24 hours. Alternatively, the free7-hydroxy containing parent compound is reacted with a mild basicreagent such as potassium carbonate, sodium carbonate, and the like, andthe cyclopentyl chloride, bromide or iodide in an inert solvent such asacetone, diethyl ketone and the like, at a temperature from about 25 C.to the reflux temperature of the solvent, and preferably at the refluxtemperature of the solvent, for from about 1 to about 24 hours.

For the preparation of the tetrahydropyran-2-yl or tetrahydrofuran-2-ylethers of Formula F of the present invention, the free 7-hydroxycontaining parent compound is reacted, under substantially anhydrousconditions, with an excess of 2,3-dihydropyran or 2,3-dihydrofuran inthe presence of a small amount of an acidic catalyst, such as borontrifluoride etherate, p-toluenesulfonic acid, ptoluenesulfonyl chlorideand the like, either alone or together with an inert organic solvent,such as benzene, diethyl ether or the like, at a temperature from aboutC. to about 50 C. and preferably at C. for from about minutes to about24 hours.

The thus-obtained novel 7-ethers of Formula P, wherein R is carboalkoxy,are used to prepare those novel ethers of the present invention, whereinR is carboxy or methylol, as shown in the following sequence:

R O R .1 H Q Z. H

R30 w R30 v wherein R is carboxy or methylol; and R, R R Z and Z are asdefined hereinabove.

For the preparation of the novel 7-ethers of Formula H, wherein R iscarboxy, the above-formed novel 7- ethers of Formula G are hydrolyzedunder basic conditions, such as for example, with sodium or potassiumhydroxide in a glycol solvent, such as ethylene glycol and the like, atthe reflux temperature of the glycol solvent for a period of about oneto about ten hours. Alternatively, the novel 7-ethers of Formula G arehydrolyzed under basic conditions with a five percent by weightalcoholic solution, such as methanol, ethanol and the like, of potassiumor sodium hydroxide under pressure, e.g, in a sealed tube, at atemperature of about 150 C. for a period of from one to about ten hours.

For the preparation of the novel 7-ethers of Formula H, wherein R ismethylol, the above-formed novel 7-ethers of Formula G are reduced bytreatment with an alkali metal hydride, such as lithium aluminum hydrideand the like, in an inert solvent, such as dioxane, tetrahydrofuran andthe like, at a tempearture of from about 25 C. to the reflux temperatureof the solvent for from about one to six hours.

The thus-obtained novel 7-ethers of Formula H, wherein R is carboxy, areused to prepare those novel ethers of the present invention, wherein Ris carbonyl chloride or carbonyl fluoride, as shown in the followingsequence:

wherein R is carbonyl chloride or carbonyl fluoride; and R R Z and Z areas defined hereinabove.

For the preparation of the novel 7-ethers of Formula I, wherein R iscarbonyl chloride, the above-formed novel 7-ether of Formula I istreated with triphenyl phosphine in carbon tetrachloride at atemperature of about 25 C. for a period of from about 1 to about 12hours, and preferably at the latter time period. Alternatively,

the novel 7-ether of Formula I is allowed to react with thionyl chlorideor oxalyl chloride in an inert halogenated solvent, such as methylenechloride, chloroform and the like, at a temperature of about 25 C. for aperiod of from 1 to 12 hours.

For the preparation of the novel 7-etl1ers of Formula J, wherein R iscarbonyl fluoride, the above-formed novel 7-ether of Formula I isallowed to react with at least a molar equivalent ofN-(2-chloro-l,1,2-trifluoroethyl)diethylamine in an inert solvent, suchas diethyl ether, acetonitrile, methylene chloride, and the like, at atemperature of from about 0 C, to about 50 C. and preferably at 25 C.for from about one hour to about ten hours, and preferably for fivehours.

The starting materials of Formula E are readily prepared by conventionaltechniques known to those skilled in the art. [See, for example, Helv.Chem. Acta, 28, 1508 (1945) and Helv. Chem. Acta, 30, 70 (1947)].

The following examples are set forth to illustrate but are not intendedto limit the scope of the present invention.

EXAMPLE 1 7-cyclopentyl ethers A solution of one chemical equivalent ofdl-cis l-ethyl- 2-methyl-Z-carboethoxy-7-hydroxy 1,2,3,4tetrahydrophenanthrene in 30 ml, of benzene is heated to reflux andabout 2 ml. removed by distillation to eliminate moisture. The mixtureis cooled to room temperature and two chemical equivalents of sodiumhydride are added, followed by the dropwise addition of two chemicalequivalents of cyclopentyl bromide in 10 ml. of benzene over a period of20 minutes. The mixture is allowed to reflux for 20 hours after whichtime the precipitate of sodium bromide is removed by filtration and theorganic phase dried and evaporated to yield dl-cis1-ethyl-2-methyl-2-carboethoxy 7 cyclopentyloxy-1,2,3,4-tetrahydrophenanthrene which is further purified uponrecrystallization from pentane.

In a similar manner, utilizing the above procedure, the followingstarting materials, namely dl-cis1-ethyl-2-methyl-2-acetoxymthyl-7-hydroxy-1,2,

3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-Z-n-propyl-2-carboethoxy-7-hydroxy-l,

2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-2-methy1-7-hydroxy-2-carboethoxy-1,2,

3,4,9,IO-hexahydrophenanthrene;

d-trans l-ethyl-2-methyl-2-carbomethoxy-7-hydroxy- 1 ,2,3 ,4,9,10,l ll2-octahydrophenanthrene; and

dl-trans l-ethyl2-methyl-2-carboethoxy-7-hydroxy-1,

2,3 ,4,9,l0,1l,12-octahydrophenanthrene;

are converted to the corresponding 7-cyclopentyloxy final products,namely dl-cis 1-ethyl-2-'methyl-2-acetoxymethyl-7-cyclopentyloxy- 1,2,3,4-tetrahyd rophenanthreue;

dl-cis l-ethyl-2-n-propy1-2-carboethoxy-7-cyclopentyloxyl- 1,2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-2-methyl-7-cyclopentyloxy-2-carboethoxy- 1,2,3 ,4,9, 1O-hexahydrophenanthrene;

d-trans 1-ethy1-Z-methyl-2carbomethoxyJ-cyclopentyl-oxy-l,2,3,4,9,10,11,12-octahydrophenanthrene; and

dl-trans1-ethyl-2-methyl-2-carboethoxy-7-cyclopentyloxy-1,2,3,4-9,10,11,12-octahydrophenanthrene.

EXAMPLE 2 Tetrahydropyranyl ethers Two milliliters of dihydropyran areadded to a solution of l g. of dl-cisl-ethyl-2-methyl-2-carboethoxy-7-hydroxy-1,2,3,4-tetrahydrophenanthrenein 15 ml. of henzene. About 1 ml. is removed by distillation to removemoisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays, and is then Washed with aqueous sodium carbonate solution andwater, dried and evaporated. The residue is chromatographed on neutralalumina, eluting with hexane, to yield dl-cis l-ethyl-2-methyl-2-carboethoxy-7-(tetrahydropyran 2 yloxy)-1,2,3,4-tetrahydrophenanthrene which is recrystallized from pentane.

In a similar manner, using the above procedure, the following startingmaterials, namely dl-cis 1-ethyl-2-methyl-2-cyano-7-hydroxy-1,2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-Z-methyl-2-amido-7-hydroxy-1,2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-2-methyl-2-carbothiomethyl-7-hydroxy-1,2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-2-methyl-Z-acetoxymethyl-7-hydroxy-1,2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-2-methyl-2-carboethoxy-7-hydroxy-1,2,3,4,9,10,11,1Z-Octahydmphenanthrene;

d-trans 1-ethyl-Z-methyl-Z-carboethoxy-7-hydroxy-1,2,3,4,9,10,11,12-octahydrophenanthrene; and

dl cis 1-ethyl-2,2-dimethyl-7-hydroxy-1,2,3,4-tetrahydrophenanthrene;are converted to the corresponding 7-(tetrahydropyran-2'-yloxy) finalproducts, namely dl-cis 1-ethyl-2-methyl-2-cyano-7-(tetrahydropyran-2-yloXy)-1,2,3 ,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-2-methyl-2-amido-7-(tetrahydropyran- 2-yloxy) -1,2,3,4-tetrahydrophenanthrene;

dl-cis1-ethyl-2-methyl-2-carbothiomethy1-7-(tetrahydropyran-2'-yloxy)-1,2,3,4-tetrahydrophenanthrene;

dl-cis1-ethyl-2-methyl-2-acetoxymethyl-7-(tetrahydropyran-2'-yloxy)-1,2,3,4-tetrahydrophenanthrene;

dl-cis1-ethyl-2-methyl-2-carboethoxy-7-(tetrahydropyran-2-yloxy)-1,2,3,4,9,10,11,12-octahydrophenanthrene;

d trans1-ethyl-2-methyl-2-carboethoxy-7-(tetrahydropyran-2'-yloxy)-1,2,3,4,9,10,11,12-octahydrophenanthrene;and

dl-cis 1-ethyl-2,2-dimethyl-7-(tetrahydropyran-2'-yloxy)-1,2,3,4-tetrahydrophenanthrene.

EXAMPLE 3 Tetradrofuranyl ethers To a solution of 1 g. of dl-cis1-ethyl-2-methyl-2-carboethoxy-7-hydroxy-1,2,3,4 tetrahydrophenanthrenein 20 ml. of benzene, is added 20 ml. of dihydrofuran. Five millilitersis distilled 011 to remove moisture, and the mixture is allowed to coolto room temperature. To the cooled mixture, 0.2 g. of freshly purifiedp-toluenesulfonyl chloride is added. The mixture is stirred at roomtemperature for 24 hours and then poured into an excess of aqueoussodium bicarbonate solution. The product is extracted with ethylacetate, the organic solution is washed with water to neutral, driedover anhydrous magnesium sulfate and evaporated to dryness under reducedpressure. The oily residue crystallizes on the addition of ether toyield the dl-cis1-ethyl-2-methyl-2-carboethoxy-7-(tetrahydrofuran-2'-yloxy)- 1,2,3,4-tetrahydrophenanthrene.

In a similar manner, utilizing the above procedure, the followingstarting materials, namely dl-cis1-ethyl-2-methyl-2-acetoxymethyl-7-hydroxy-1,2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-2-methyl-2-acetyl-7-hydroxy-1,2,3,4-tetrahydrophenanthrene;

dl-cis 1-ethyl-Z-methyl-Z-formyl-7-hydroxy1,2,3,4-tetrahydrophenanthrene;

dl-trans 1-ethyl-2-methyl-2-carbomethoxy-7-hydroxy-1,2,3,4,'9,l0,11,l2-hexahydrophenanthrene; and

d-trans l-ethyl-2-methyl-2-carboethoxy-7-hydroxy-1,2,3,4,9,10,11,12-octahydrophenanthrene; are converted to thecorresponding 7-(tetrahydrofuran-2'- yloxy) final products, namelydl-cis 1-ethyl-2-methyl-2-acetoxymethyl-7-(tetrahydro- 6furan-2'-yloxy)-1,2,3 ,4-tetrahydrophenanthrene; dl-cis1-ethyl-2-methyl-2-acetyl-7-(tetrahydrofuran-2-yloxy)-1,2,3,4-tetrahydrophenanthrene; dl-cis1-ethyl-2-methyl-2-formy1-7-(tetrahydrofuran-2'-yloxy)-1,2,3,4-tetrahydrophenanthrene;dl-trans1-ethyl-2-methyl-2-carbomethoxy-7-(tetrahydrofurgm-Z-yloxy)-1,2,3,4,9,10-hexahydrophenanthrene;an d-trans1-ethyl-2-methyl-2-carboethoxy-7-(tetrahydrofuran-2-yloxy)-1,2,3,4,9,10,11,12-0ctahydrophenanthrene.

EXAMPLE 4 Z-phenanthrenecarboxylic acids A solution of 1 g. of di-cis1-ethyl-2-methyl-2-carboethoxy7-cyclopentyloxy-1,2,3,4-tetrahydrophenanthrene in 50 ml. of ethyleneglycol is heated at reflux for three hours with a solution of potassiumhydroxide in 1 ml. of water. The reaction mixture is then poured intoice water and the solid which forms is collected by filtration, washedwith water to neutrality and dried to yield dl-cis1-ethyl-2-methyl-7-cyclopentyloxy 1,2,3,4 tetrahydro-2-phenanthrenecarboxylic acid which is recrystallized from methvlenechloride ether.

In a similar manner, utilizing the above procedure, the followingstarting materials, namely EXAMPLE 5 2-phenanthrenecarboxylic acidfluoride A solution of 1 g. of dl-cis 1-ethyl-2-methyl-7-cyclopentyloxy1,2,3,4 tetrahydr0-2-phenanthrenecarboxylic acid in 30 ml. of anhydrousmethylene chloride is allowed to react with 1 g. ofN-(2-chloro-1,1,2-trifluoroethyl) diethylamine. The reaction mixture isheated under reflux for a period of five hours. The mixture is thenpoured into ice water, and the product extracted with ether. Theextracts are dried and evaporated to dryness to yield the dl-cis l-ethyl2 methyl-7-cyclopentyloxy-1,2,3,4-tetrahydro-2-phenanthrenecarboxylicacid fluoride which is recrystallized from acetonezhexane.

In a similar manner, using the above procedure, the following materials,namely dl-cis 1-ethyl-2-methyl-7- (tetrahydrofuran-2'-yloxy)1,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid;

dl-cis 1ethyl-2-methyl-7-(tetrahydropyran-2'-yloxy)-1,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid;

d-trans 1-ethyl-2-methyl-7- (tetrahydropyran-2-yloxy1,2,3,4,9,10,11,12-octahydro-2-phenanthrenecarboxylic acid;

7 dl-cis 1-ethyl-2-methyl-7- (cyclopentyloxy)-1,2,3,4,9,10,

1 1,12-octahydro-2phenanthrenecarboxylic acid; and dl-cisl-ethyl-2-methyl-7-(tetrahydrofuran-2'-yloxy)- 1,2,3,4,9,10-hexahydro2-phenanthrenecarboxylic acid; are converted to thecorresponding Z-acid fluoride final products, namely dl-cisl-ethyl-2-methyl-7-(tetrahydrofuran-2-yloxy)- 1,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid fluoride;

dl-cis l-ethyl-Z-methyl-7-(tetrahydropyran-2'-yloxy)-1,2,3,4-tetrahydro-2-phenanthrenecarboxylic acid fluoride;

d-trans 1-ethyl-2-methyl-7(tetrahydropyran-2-yloxy)- 1,2,3,4,9, 10,1 1,l2-octahydro-2-phenanthrenecarboxylic acid fluoride;

dl-cis 1-ethyl-2-methyl-7- cyclopentyloxy l ,2,3 ,4,9,10,

11,12-octahydro-Z-phenanthrenecarboxylic acid fluoride; anddl-cisl-ethyl-2-methyl-7-(tetrahydrofuran-2'-yloxy)-l,2,3,4,9,10-hexahydro-Z-phenanthrenecarboxylic acid fluoride.

EXAMPLE 6 Z-methylolphenanthrenes A solution of 1 .g. of dl-cisl-ethyl-Z-methyl-Z-carboethoxy 7(tetrahydropyran-Z'yloxy)-l,2,3,4-tetrahydrophenanthrene in 50 ml. oftetrahydrofuran is added over a 30 minute period to a stirred suspensionof l g. of lithium aluminum hydride in 50 ml. of anhydroustetrahydrofuran and this mixture is heated at reflux for two hours. Tothe mixture are cautiously added ml. of ethyl acetate and 2 m1. ofwater. Sodium sulfate is next added, the mixture is filtered and thesolid thus collected is washed with hot ethyl acetate. The combinedorganic solutions are then evaporated to yield dl-cis l-ethyl-Z- methyl2 methylol-7-(tetrahydropyran-Z-yloxy) 1,2- 3,4-tetrahydrophenanthrenewhich may be further purified through recrystallization fromacetonezhexane.

In a similar manner, using the above procedure, namely dl-cis1ethyl-2-methyl-2-carboethoxy-7-(cyclopentyloxy)-1,2,3,4-tetrahydrophenanthrene; and dl-cis1-ethyl-Z-methyl-Z-carboethoxy-7-(tetrahydrofuran-2-yloxy)-1,2,3,4-tetrahydrophenanthrene; are converted to thecorresponding Z-methylol final products, namely dl-cis1ethyl-2methyl-2-methylol-7-(cyclopentyloxy)1,2,3,4-tetrahydrophenanthrene; and

dl-cis 1ethyl-2-methyl-2-methyl01-7-( tetrahydrofuran-2'-yloxy)-1,2,3,4-tetrahydrophenanthrene.

EXAMPLE 7 2-phenanthrenecarboxylic acid chloride A solution of 1 g. ofdl-cis 1-ethyl-2-methyl-7-cyclopentyloxy-l,2,3,4-tetrahydro 2phenanthrenecarboxylic acid in ml. of carbon tetrachloride is allowed toreact with 2 g. of triphenylphosphine. The reaction mixture is held atC. for a period of twelve hours. The mixture is then poured into icewater, filtered and the product is extracted with ether. The extractsare dried and evaporated to dryness to yield dl-cis1ethyl-2-methyl7-cyclopentyl oxy 1,2,3,4tetrahydro2-phenanthrenecarboxylic acid chloride which is purified bychromatography over florisil and recrystallized from acetonezhexane.

In a similar manner, using the above procedure, namely dl-cis1-ethyl-2-methyl-7-,tetrahydrofuran-Z'-yloxy)-1,2,3,4-tetrahydro2-phenanthrenecarboxylic acid;

dl-cis 1-ethyl-2-methyl-7-(tetrahydropyran-2'-yloxy)1,2,3,4tetrahydro2-phenanthrenecarboxylic acid;

d-trans 1-ethyl-2-methyl-7- (tetrahydropyran-2'-yloxy 1,2,3,4,9, 10,1 1,l2-octahydro-2-phenanth renecarboxylic acid;

dl-cis 1ethyl-2-methyl-7-(cyclopentyloxy)-l,2,3,4,9,10,

11,12-octahydro-2-phenanthrenecarbovxylic acid; and

dl-cis l-ethyl-2-methyl-7-(tetrahydrofuran-2-yloxy)- 81,2,3,4,9,10-hexahydro-Z-phenanthrenecarboxylic acid; are converted tothe following acid chloride final products, namely dl-cisl-ethyl-2-methyl-7-(tetrahydrofuran-2-yloxy)-1,2,

3,4-tetrahydro-Z-phenanthrenecarboxylic acid chloride;

dl-cis l-ethyl-2-methyl-7- (tetrahydrofur an-2-yloxy1,2,3,4-tetrahydro-Z-phenanthrenecarboxylic acid chloride;

d-trans 1-ethyl-2-methyl-7-(tetrahy-dropyran-2-yloxy)- 1,2,3,4,9, 10,1l,12-octahydro-2-phenanthrenecarboxylic acid chloride;

dl-cis 1-ethyl-2-methy1-7-(cyclopentyloxy) -1,2,3,4,9, 10,1 1,

1Z-octahydro-2-phenanthrenecarboxylic acid chloride; and

dl-cis 1-ethyl-2-rnethyl-7-(tetrahydropyran-2-yl0xy)-1,2,3,4,9,10-hexahydro-Zphenanthrenecarboxylic acid chloride.

What is claimed is: 1. A compound according to the following formulas:

M0 11 H H R r M 2 ".32 3 M0 wherein R is lower alkyl of one to threecarbon atoms;

R is carboxy, COOR wherein R is alkyl of one to three carbon atoms; and

R is cyclopentyl.

2. A compound according to Formula A of claim 1 wherein R is methyl; Ris carboxy.

3. A compound according to Formula D of claim 1 wherein R is methyl; Ris carboxy.

4. A compound according to Formula A of claim 1 wherein R is methyl andR is COOR wherein R is ethyl.

5. A compound according to Formula A of claim 1 wherein R is n-propyland R is COOR wherein R is ethyl.

6. A compound according to Formula D of claim 1 wherein R is methyl andR is COOR wherein R is methyl.

7. A compound according to Formula D of claim 1 wherein R is methyl andR is COOR wherein R is ethyl.

References Cited UNITED STATES PATENTS 2,687,426 8/1954 Hogg 260514.5 X

LORRAINE A. WEINBERGER, Primary Examiner P. I. KILLOS, AssistantExaminer US. Cl. X.R.

260345.7, 345.8, 345.9, 347.3, 347.4, 347.8, 455 C, 465 F, 488 CD,514.5, 544 F, 544 M, 559 R, 586 H, 600, 612 R, 613 R; 424308 DIG 12UMTED STATES PATENT OFFICE CEER'EEIFICATE OF CORRECTION Patent No. 3,636,071

Dated January 18, 1972 Inventor(s) John A. Edwards It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 4, line 18, "70" should be 780 Column 4, line 42,"2-acetoxymthyl-" should be 2-acetoxymethyl- 4 Column 4, line 58, "oxyl"should be oxy- Column 5, line 70, "l, 2, 3,4,9, 10, ll,l2hexahydrophenanthren and" should be l, 2, 3, 4,9,lO-hexahydrophenanthrene7 and Column 6, line 30, "2carbethoxy-7" shouldbe 2carbOethoXy-7 Column 7, line 36, (tetrahydropyran-Z-yloxy) should be(tetrahydropyran-Z yloxy) Column 8, Claim 1, formula B, omitted.

Column 8, Claim 1, I formula C should appear as follows in brackets,should be Signed and sealed this 5th day of September 1972.

(SEAL) Attest:

FDWAPD N .FLETCHER,JR. Attesting Officer ROBERT GOTTSCHALK Commissionerof Patents I PC4050 (IO-69)

